On/Off Androgen Ablation Matches Nonstop Therapy

Action Points

Explain that intermittent androgen suppression was found to be non-inferior to continuous suppression in asymptomatic men with rising PSA after radiotherapy for localized prostate cancer.

Note that those receiving intermittent therapy had improved quality of life on some sexual outcomes such as hot flashes and libido.

Intermittent androgen deprivation therapy (ADT) proved to be as effective as continuous treatment and improved quality of life for asymptomatic men with rising PSA levels after definitive prostate cancer treatment, a large randomized trial showed.

Median overall survival was 8.8 years with intermittent therapy and 9.1 years with continuous therapy, and the 7-year estimated disease-related mortality was 18% and 15%, respectively. Neither difference was statistically significant.

Men who received intermittent therapy appeared to benefit on several functional, symptomatic, and sexual outcomes, as reported in the Sept. 6 issue of the New England Journal of Medicine.

"The longer-than-expected median survival of 9 years for all patients with biochemical evidence of disease progression supports the need for a reduction in the toxicity of treatment," Juanita M. Crook, MD, of the British Columbia Cancer Agency in Kelowna, British Columbia, and co-authors wrote in conclusion.

"However, the finding that overall survival was not reduced by using the study-defined intermittent androgen-deprivation approach should not be extrapolated to other treatment schedules," they wrote. "In addition, this trial did not address the question of when, or at what PSA level, treatment should be initiated."

The concept of intermittent ADT -- cycling patients on and off to stall progression to castration-resistant status -- dates back to the 1980s and intermittent use of diethylstilbestrol. Subsequently, an accumulation of experimental data showed that hormone-dependent cells would undergo multiple cycles of apoptosis in response to cyclic hormonal treatment.

After demonstrating proof of principle in animal models of prostate cancer, investigators in phase II trials extended the proof to humans. The positive results of those trials led to the phase III study conducted in North America and England by the National Cancer Institute of Canada and reported by Crook and colleagues.

Men randomized to intermittent therapy stopped treatment after 8 months and were followed at 2-month intervals. They remained off treatment so long as PSA values remained <4 ng/mL and within 1 ng/mL of the previous measurement.

The trial had a primary endpoint of overall survival. Secondary endpoints consisted mostly of quality-of-life factors. The trial ended prematurely when a planned interim analysis showed that the threshold for noninferiority of intermittent therapy had been reached.

The primary analysis included 1,386 men. When the trial ended, the small difference in overall survival translated into a hazard ratio of 1.02 for intermittent versus continuous therapy, which exceeded the prespecified hazard ratio of <1.25 (P=0.009).

A multivariable proportional-hazards model also showed no survival difference after adjustment for age, performance status, time since radiation therapy, treatment with neoadjuvant hormonal therapy, and baseline PSA values. Similarly, a model limited to assigned treatment and Gleason score (≤6, 7, or 8 to 10) found no difference between treatment groups.

Almost 60% of deaths in the trial were unrelated to prostate cancer. Investigators retrospectively analyzed data after exclusion of nonprostate cancer deaths, and the hazard ratio remained within the threshold for non-inferiority.

Progression to castration-resistant prostate cancer (CRPC) occurred in 202 patients in the intermittent-therapy arm and in 243 patients who received continuous therapy. The difference represented a statistically significant 20% reduction in the hazard for CRPC in favor of intermittent therapy (HR 0.80, P=0.02).

Patients randomized to continuous therapy had a median treatment duration of 43.9 months, compared with 15.4 months among men who received intermittent therapy.

Testosterone recovery to normal levels occurred in 35% of men treated with intermittent therapy, but 79% had recovery to baseline levels. Among men who were sexually potent at baseline, 29% had recovery of potency with intermittent therapy.

The trial represents "the most definitive study to date comparing intermittent versus continuous androgen-deprivation therapy," Oliver Sartor, MD, of Tulane University in New Orleans, wrote in an accompanying editorial.

However, he noted, the trial left unanswered the question of which patients might not require any hormonal therapy.

"It is still unclear which men with rising PSA levels needed treatment," Sartor wrote. "This is a heterogeneous patient group, and only a minority of men might be expected to have clinical consequences from their rise in PSA level. Given the slow progression of prostate cancer in many men, which of these asymptomatic patients actually benefited from androgen-deprivation therapy?"

The trial also did not address the question of timing of ADT, intermittent or otherwise, for asymptomatic men, according to Sartor.

"Does early androgen-deprivation therapy in asymptomatic men with rising PSA levels provide more benefit than treatment in symptomatic men with metastases? This question bedevils our field, and we are no closer to an answer now than we were before," he wrote.

The trial was supported by the Canadian Cancer Society Research Institute, the U.S. National Cancer Institute, and Hoechst Marion Roussel Canada Research.

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